The invention relates to the use of defined linear peptides in the treatment of diabetic and other non-HIV neuropathic pain syndromes.
Several pain syndromes associated with disorders of the peripheral and central nervous system ("neuropathic pain") exist and few if any effective treatments for such pain are known.
Patients with such conditions make up a large proportion of those whose pain remains resistant to current therapies. Among the most common causes are the neuropathies associated with diabetes, cancer chemotherapy, herpes zoster, cervical or lumbar root compression owing to degenerative spine disease, malignant lesions of nerve plexus or root, nerve trauma, including amputation, HIV infection, and lesions of central pain pathways, including spinothalamic tract, thalamus, or thalamic radiations [Max, M. B., "Neuropathic Pain Syndromes", in Advances in Pain Research and Therapy, V18 (ed. M. Max et al) Raven Press, New York, 1991]. Drug-induced, or toxic, neuropathies have also been described. Thus the antivirals ddI and ddC commonly cause peripheral neuropathies, as do Vincristine (a cancer chemotherapeutic agent), Dilantin (a seizure medication), high dose vitamins, Isoniazid (a tuberculosis medication), and folic acid antagonists.
Patients' symptoms may include the unusual sensations of burning, tingling, electricity, pins and needles, stiffness, numbness in the extremities, feelings of bodily distortion, allodynia (pain evoked by innocuous stimulation of the skin), and hyperpathia (an exaggerated pain response persisting longs after pain stimuli cease).
The neuropathic pain syndromes result, apparently, from a variety of lesions and appear to encompass a mixed group of underlying physiological abnormalities. However, recent findings and treatment modalities have begun to suggest the existence of a common, unifying defect for a number of pain syndromes. As this may now be envisioned to occur, novel treatments which reverse or restore the normal functioning of the seemingly diverse lesions may be envisioned with efficacy against many diverse neuropathies.
The underlying basis for this new conception relates to evidence that a specific growth factor or neurotrophin, secreted by neurons, glia, neighboring parenchymal cells, or in endocrine fashion, is needed to support and maintain the normal functioning and viability of sensory neuronal pathways, either in the periphery or the brain. Pathologies caused by different mechanisms or etiologic agents, as detailed above, may have as a common convergence the loss or diminution of the needed neurotrophin. This then results in Wallerian type degeneration, nerve dystrophy or other dysfunctional or neurophysiological abnormality, the end result being hyperalgesia and enhanced pain nociception.
The synthesis of peptide T and its use in the treatment of mental disorders and memory deficits not caused by HIV infection has been disclosed in U.S. Pat. No. 5,063,206, the disclosure of which is incorporated herein by reference.
Recently it has been reported (Brenneman et al, Peptide T prevents gp120 induced neuronal cell death in vitro:relevance to AIDS dementia, Drug Dev. Res. 15:361-369, 1988.) that peptide T, which has structural relatedness to the neurotrophin vasoactive intestinal peptide (VIP), also will act to maintain the growth and viability of neurons in culture dishes. Structure-activity studies indicate that this activity of peptide T is due to a specific homology with VIP.
Additionally, peptide T has been reported to have benefit in the neurological pain (MacFadden et al, (abstr) Role of peptide T in palliation of HIV-1 related painful peripheral neuropathy, VII Intnat Conf AIDS (Firenze) 1991 #W.B.217) caused by HIV infection. However, unlike the treatment of diabetic and other non-HIV neuropathic pain syndromes, in the treatment of HIV-related painful peripheral neuropathy, the function of peptide T is to block the toxic actions of virally derived proteins on the nervous system.